This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Small molecules are valuable as tool compounds for biomedical research and as the beginning of drug discovery programs. High-throughput screening (HTS) provides a platform for the identification of commercial compound "hits" having some desired biological properties, but truly useful compounds almost always require fine-tuning through reiterative analogue design and synthesis. A Medicinal Chemistry Core (MDC) is proposed to carry out these activities in conjunction with the work of the HTS Core and in collaboration with the COBRE Center and other researchers. The tasks of the Medicinal Chemistry Core will be (1) to perform synthesis of known compounds necessary for biochemical studies, (2) to design and synthesize novel drug compounds as probes for ongoing studies, (3) to work with the HTS Core and its biology collaborators in carrying out optimization of hits obtained in screening campaigns, and (4) to synthesize fluorescent or affinity tagged analogs of existing probes when necessary for cell localization or target identification studies. A Medicinal Chemistry Core (MDC)will fine-tune compounds through reiterative analogue design and synthesis in conjunction with the work of the HTS Core and in collaboration with the COBRE Center and other researchers.